Illicit cocaine use continues to be a pervasive problem in the United States; the State of Texas cites cocaine abuse as its greatest illicit drug threat. Cocaine intoxication, dependence and withdrawal are marked by psychological (e.g., euphoria, depression, anxiety, anhedonia, craving) and physiological symptoms (e.g., fatigue, hyperphagia, anergia). An elucidation of the neural mechanisms that underlie the in vivo effects of cocaine is required in order to design effective psycho- and pharmacotherapeutic approaches to the treatment of cocaine addicts. The behavioral effects of cocaine are critically dependent upon mesocorticolimbic circuits, particularly the pathway that originates in dopamine (DA) cell bodies in the ventral tegmental area and terminates in the nucleus accumbens. Serotonin (5-hydroxytryptamine, 5-HT) is involved in the etiology of psychotic (e.g., schizophrenia), affective (e.g., anxiety, depression) and somatic disorders (e.g., obesity). The innervation and localization of 5-HT1B, 5-HT2C or 5-HT4 receptors in mesocorticolimbic circuits and the ability of cocaine to inhibit 5-HT reuptake suggest that 5-HT contributes to the in vivo effects of cocaine. The current literature and our preliminary data support differential roles of each receptor in modulating spontaneous and cocaine-stimulated behavior. In the present proposal, the role of 5-HT1B (Aim 1), 5-HT2C (Aim 2) and 5-HT4 receptors (Aim 3) in the locomotor stimulant and discriminative stimulus effects of cocaine will be investigated using novel ligands and receptor knockdown techniques. The pattern of immediate early gene expression in the presence vs. absence of receptor-specific ligands will be employed to localize the site of action of each receptor. Based upon these maps, microinfusions of 5-HT1B, 5-HT2C or 5-HT4 receptor ligands or antisense oligonucleotides will be targeted to identified mesocorticolimbic nuclei in order to clarify the site of action for each receptor in spontaneous and cocaine-evoked behaviors. Modifications in 5-HT1B, 5-HT2C and 5-HT4 receptors during withdrawal will also be established via analysis of behavior and levels of receptor mRNA and protein expression in brain at several time-points following termination of intermittent cocaine exposure. The experiments outlined will yield significant information concerning the interplay between 5-HT receptors and cocaine, elucidate the manner in with 5-HT controls DA in vivo and help to define the specific and unique roles of these receptors in behavior. As a consequence, new insight into the potential therapeutic strategies for cocaine dependence and a number of psychiatric disorders dependent upon normal 5-HT function will be gained.